MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS

描述(由申请人提供)： 尽管烧伤早期液体复苏、早期切除和移植，以及使用局部和全身抗菌剂来控制伤口感染的情况不断改善，但与烧伤相关的真皮丢失对烧伤患者的感染风险很大。吸入性损伤、插管和需要长时间的通风会导致肺炎的大量发生，这种肺炎往往会发展为多器官衰竭，这种综合征的死亡率为50%。烧伤创伤后脓毒症的发展可能会加剧炎症反应和与初始损伤相关的器官功能障碍，这一直是临床上关注的问题。大量研究描述了创伤和脓毒症时的心肌功能障碍，但确切的细胞机制仍不清楚。心肌抑制的一个共同特征是心肌细胞内钙离子([Ca~(2+)]i)的积聚。上一次资助期间的时间进程研究证实，烧伤或脓毒症相关的心肌细胞内Na+的积累先于细胞内钙的升高，提示心肌细胞内Na+的积累可能是心肌细胞钙超载的先决条件。本文提出的研究将检验一种总体假设，即心肌细胞的Na+积累是烧伤或脓毒症后的初始事件，并通过PKC依赖的途径发生；Na+负荷反过来促进心肌细胞的Ca~(2+)负荷；由于特定的Ca~(2+)转运蛋白的表达和功能改变，心肌细胞的Ca~(2+)稳态持续，即Na~+-Ca~(2+)交换器和SERCA的变化可能减少心肌细胞的Ca~(2+)外流。线粒体和核钙离子的积累导致这些细胞器的损伤，产生自由基，改变DNA含量和完整性，导致心肌细胞凋亡和心肌功能障碍。我们进一步假设，烧伤或脓毒症相关的心肌损伤和功能障碍的恢复与DNA切除修复和心肌细胞复制有关。拟议的工作集中在五个具体目标上，以增加我们对烧伤和脓毒症相关心肌损伤所涉及的细胞事件的了解。

DESCRIPTION (provided by applicant): Despite continued improvements in early fluid resuscitation from burn trauma, early excision and grafting, and the use of both local and systemic antimicrobials to control wound infection, burn-related loss of the dermis poses a significant risk for infection in the burn patient. Inhalation injury, intubation and the need for prolonged ventilation contribute to a significant incidence of pneumonia that often progresses to multiple organ failure, a syndrome that carries a mortality rate of 50%. A persistent clinical concern is that the development of sepsis after burn trauma may exacerbate inflammatory responses and organ dysfunction associated with the initial injury. Numerous studies describe myocardial dysfunction in trauma and sepsis, but the precise cellular mechanisms remain unclear. One common feature of myocardial depression is the accumulation of cytosolic calcium ([Ca2+]i) by cardiomyocytes. Time course studies during the previous funding period confirmed that burn- or sepsis-related myocyte accumulation of Na+ precedes the rise in cellular Ca2+, suggesting that cardiomyocyte accumulation of Na+ may be a prerequisite for myocyte Ca2+ overload. The studies proposed herein will examine the overall hypothesis that Na+ accumulation by the cardiomyocytes is an initial event after burn trauma or sepsis and occurs via a PKC dependent pathway; Na+ loading, in turn, promotes myocyte Ca2+ loading; myocyte Ca2+ dyshomeostasis persists due to altered expression and function of specific Ca2+ transport proteins, i.e., alterations in Na+-Ca2+ exchanger and SERCA may decrease Ca2+ efflux from the myocytes. Mitochondrial and nuclear Ca2+ accumulation contribute to injury of these cellular organelles, producing free radical generation, altered DNA content and integrity, myocyte apoptosis and myocardial dysfunction. We further hypothesize that recovery from burn or sepsis-related myocardial injury and dysfunction is related to DNA excisional repair as well as myocyte replication. The proposed work focuses on five specific aims to increase our understanding of the cellular events involved in burn and sepsis-related myocardial injury.